tbuckley/cabot-search huggingface dataset:
Higher native Peruvian genetic ancestry proportion is associated with tuberculosis progression risk
Authors: Samira Asgari, Yang Luo, Chuan-Chin Huang, Zibiao Zhang, Roger Calderon, Judith Jimenez, Rosa Yataco, Carmen Contreras, Jerome T. Galea, Leonid Lecca, David Jones, D. Branch Moody, Megan B. Murray, Soumya Raychaudhuri
Journal: Cell Genomics (2022)

We investigated whether ancestry-specific genetic factors affect tuberculosis (TB) progression risk in a cohort of admixed Peruvians. We genotyped 2,105 patients with TB and 1,320 household contacts (HHCs) who were infected with Mycobacterium tuberculosis (M. tb) but did not develop TB and inferred each individual's proportion of native Peruvian genetic ancestry. Our HHC study design and our data on potential confounders allowed us to demonstrate increased risk independent of socioeconomic factors. A 10% increase in individual-level native Peruvian genetic ancestry proportion corresponded to a 25% increased TB progression risk. This corresponds to a 3-fold increased risk for individuals in the highest decile of native Peruvian genetic ancestry versus the lowest decile, making native Peruvian genetic ancestry comparable in effect to clinical factors such as diabetes. Our results suggest that genetic ancestry is a major contributor to TB progression risk and highlight the value of including diverse populations in host genetic studies.
A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma
Authors: Phillip M. Rappold, Lynda Vuong, Josef Leibold, Nicholas H. Chakiryan, Michael Curry, Fengshen Kuo, Erich Sabio, Hui Jiang, Briana G. Nixon, Ming Liu, Anders E. Berglund, Andrew W. Silagy, Eduardo A. Mascareno, Mahdi Golkaram, Mahtab Marker, Albert Reising, Alexander Savchenko, John Millholland, Ying-Bei Chen, Paul Russo, Jonathan Coleman, Ed Reznik, Brandon J. Manley, Irina Ostrovnaya, Vladimir Makarov, Renzo G. DiNatale, Kyle A. Blum, Xiaoxiao Ma, Diego Chowell, Ming O. Li, David B. Solit, Scott W. Lowe, Timothy A. Chan, Robert J. Motzer, Martin H. Voss, A. Ari Hakimi
Journal: Cancer Discovery (2022)

Abstract It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC. Significance: Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model. This article is highlighted in the In This Issue feature, p. 2221
Sustained drug delivery strategies for treatment of common substance use disorders: Promises and challenges
Authors: Akeemat O. Tijani, Jivesh Garg, Dorcas Frempong, Gabrielle Verana, Jagroop Kaur, Ramesh Joga, Chetan D. Sabanis, Sandeep Kumar, Neeraj Kumar, Ashana Puri
Journal: Journal of Controlled Release (2022)
Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery
Authors: Luregn J. Schlapbach, Kristen S. Gibbons, Stephen B. Horton, Kerry Johnson, Debbie A. Long, David H. F. Buckley, Simon Erickson, Marino Festa, Yves d’Udekem, Nelson Alphonso, David S. Winlaw, Carmel Delzoppo, Kim van Loon, Mark Jones, Paul J. Young, Warwick Butt, Andreas Schibler, Johnny Millar, Kate Masterson, John Beca, Taryn Evans, Shelley Coetzer, Claire Sherring, Jennifer Darvas, Killian O'Shaughnessy, Chong Tien Goh, Gail Harper, Sam Barr, Rae Kelly, Hannah Thomson, Kelly Holmes, Nigel Slade, David Andrews, Carla Zazulak, Benjamin Anderson, Antje Blumenthal, Jonas Fooken, Endrias Ergetu, Brenda Gannon, Renate Le Marsney, Trang Pham, Annelies Hennink, Erik Koomen, Nicole J.C.W. van Belle-van Haaren, Bram van Wijk
Journal: JAMA (2022)

In children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation).
Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia
Authors: Steven M. Paul, Samantha E. Yohn, Michael Popiolek, Andrew C. Miller, Christian C. Felder
Journal: American Journal of Psychiatry (2022)

Schizophrenia remains a challenging disease to treat effectively with current antipsychotic medications due to their limited efficacy across the entire spectrum of core symptoms as well as their often burdensome side-effect profiles and poor tolerability. An unmet need remains for novel, mechanistically unique, and better tolerated therapeutic agents for treating schizophrenia, especially those that treat not only positive symptoms but also the negative and cognitive symptoms of the disease. Almost 25 years ago, the muscarinic acetylcholine receptor (mAChR) agonist xanomeline was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimer's disease. The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia. These unexpected clinical findings have prompted considerable efforts across academia and industry to target mAChRs as a new approach to potentially treat schizophrenia and other psychotic disorders. The authors discuss recent advances in mAChR biology and pharmacology and the current understanding of the relative roles of the various mAChR subtypes, their downstream cellular effectors, and key neural circuits mediating the reduction in the core symptoms of schizophrenia in patients treated with xanomeline. They also provide an update on the status of novel mAChR agonists currently in development for potential treatment of schizophrenia and other neuropsychiatric disorders.
Temporality of body mass index, blood tests, comorbidities and medication use as early markers for pancreatic ductal adenocarcinoma (PDAC): a nested case–control study
Authors: Pui San Tan, Cesar Garriga, Ashley Clift, Weiqi Liao, Martina Patone, Carol Coupland, Rachael Bashford-Rogers, Shivan Sivakumar, Julia Hippisley-Cox
Journal: Gut (2022)

Prior studies identified clinical factors associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). However, little is known regarding their time-varying nature, which could inform earlier diagnosis. This study assessed temporality of body mass index (BMI), blood-based markers, comorbidities and medication use with PDAC risk .We performed a population-based nested case-control study of 28 137 PDAC cases and 261 219 matched-controls in England. We described the associations of biomarkers with risk of PDAC using fractional polynomials and 5-year time trends using joinpoint regression. Associations with comorbidities and medication use were evaluated using conditional logistic regression.Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while following a U-shaped relationship for BMI and haemoglobin. Five-year trends showed biphasic BMI decrease and HbA1c increase prior to PDAC; early-gradual changes 2-3 years prior, followed by late-rapid changes 1-2 years prior. Liver markers and blood counts (white blood cell, platelets) showed monophasic rapid-increase approximately 1 year prior. Recent diagnosis of pancreatic cyst, pancreatitis, type 2 diabetes and initiation of certain glucose-lowering and acid-regulating therapies were associated with highest risk of PDAC.Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while followed a U-shaped relationship for BMI and haemoglobin. BMI and HbA1c derange biphasically approximately 3 years prior while liver markers and blood counts (white blood cell, platelets) derange monophasically approximately 1 year prior to PDAC. Profiling these in combination with their temporality could inform earlier PDAC diagnosis.
Double-blinded randomised placebo controlled trial of enterosgel (polymethylsiloxane polyhydrate) for the treatment of IBS with diarrhoea (IBS-D)
Authors: Carol Angela Howell, Anu Kemppinen, Victoria Allgar, Matthew Dodd, Charles H Knowles, John McLaughlin, Preeti Pandya, Peter Whorwell, Elena Markaryan, Yan Yiannakou
Journal: Gut (2022)

Objective Irritable bowel syndrome with diarrhoea (IBS-D) is a common and challenging condition that significantly reduces quality of life. Enterosgel (polymethylsiloxane polyhydrate) is an intestinal adsorbent which sequesters harmful molecules and is safe and effective in acute infective diarrhoea. This randomised controlled multicentre trial aimed to investigate its safety and efficacy in patients with IBS-D. Design After a 2-week screening phase, participants were randomised into an 8-week double-blind phase, followed by an 8-week open-label and follow-up phase. Participants recorded stool consistency, pain and global symptoms in e-diaries and questionnaires. The primary outcome was the percentage of responders on a composite abdominal pain (≥30% decrease in the weekly score) and stool consistency (50% reduction in days per week with at least one stool of BSFS type 6 or 7) score during at least 4 weeks of the treatment period. Results 440 patients with IBS-D were randomised to the double-blind phase with 393 continuing to the open-label phase. The Primary outcome responder rate by intention-to-treat for enterosgel versus placebo was 37.4% vs 24.3% (OR 1.95, NNT 8, p=0.002). Enterosgel also improved stool consistency (48.5% vs 32.5%, p&lt;0.0001) abdominal pain (53.3% vs 40.2%, p=0.003), stool frequency (treatment effect −0.32 (−0.62 to −0.02)) and urgency (treatment effect −0.59 (−0.85 to −0.33)). 60% of patients reported adequate relief of symptoms after open-label treatment. Adverse event frequency was similar in both groups, with no serious events attributable to enterosgel. Conclusion Enterosgel is safe and effective in IBS-D, providing an alternative to the limited current treatment options. Trial registration number ISRCTN17149988 .
OP0006 CLEANING ACTIVITIES, DUSTY CLOTHES LAUNDRY AND TALCUM HANDLING ARE UNDERESTIMATED MAJOR SOURCES OF EXPOSURE TO CRYSTALLINE SILICA IN WOMEN WITH RHEUMATOID ARTHRITIS
Authors: J. Sigaux, C. Cavalin, A. Lescoat, P.Y. Brillet, L. Sese, H. Nunes, M.C. Boissier, L. Semerano
Journal: Annals of the Rheumatic Diseases (2022)

<h3>Background</h3> Inhalation of crystalline silica (cSiO<sub>2</sub>) is associated with rheumatoid arthritis (RA). Research on cSiO<sub>2</sub> has historically focused on professional exposures and on male workers. However, cSiO<sub>2</sub> is ubiquitously present in the environment, substantial exposure can take place in both men and women, in other professional activities and even beyond occupational context. <h3>Objectives</h3> To identify the main sources of exposure to crystalline silica in a series of RA patients not selected based on their professional activity, and to assess the association between silica exposure and disease features. <h3>Methods</h3> The Dust Exposure Life-Course Questionnaire (DELCQ) is a novel tool that longitudinally quantifies both occupational and non-occupational lifetime exposure to crystalline silica. The DELCQ was previously validated in a representative sample of the general French population that serves as control source for studies in specific diseases. The DELCQ was administered to 97 consecutive patients with RA, exposure scores were compared between cases and age-, sex- and smoking status-matched controls (1:4). The main sources of silica exposure were identified in cases and controls and source-specific exposure levels compared. The association between DELCQ scores and disease variables in cases was tested at uni- and multivariable analysis. <h3>Results</h3> In women with RA, the main sources of crystalline silica exposure were: cleaning activities, dusty clothes laundry and talcum powder handling, with higher exposure levels from these sources vs. the general population (p&lt;0.005). In the whole series of RA patients, high silica exposure was independently associated with interstitial lung disease (OR 6.5 (95% CI: 1.3 to 32.6)) and mediastinal lymphadenopathy (OR 6.3 (95% CI: 1.4 to 27.7). <h3>Conclusion</h3> Cleaning activities, dusty clothes laundry and talcum handling are underestimated sources of crystalline silica exposure that are overrepresented in women with RA compared to the general population and may contribute to the pathogenesis of the disease. <h3>Disclosure of Interests</h3> None declared.
Facial amphiphilicity index correlating chemical structures with antimicrobial efficacy
Authors: Leman Buzoglu Kurnaz, Yuanyuan Luo, Xiaoming Yang, Amjed Alabresm, Ryan Leighton, Rani Kumar, JiHyeon Hwang, Alan W. Decho, Prakash Nagarkatti, Mitzi Nagarkatti, Chuanbing Tang
Journal: Bioactive Materials (2022)

Facial amphiphilicity is an extraordinary chemical structure feature of a variety of antimicrobial peptides and polymers. Vast efforts have been dedicated to small molecular, macromolecular and dendrimer-like systems to mimic this highly preferred structure or conformation, including local facial amphiphilicity and global amphiphilicity. This work conceptualizes Facial Amphiphilicity Index (FAI) as a numerical value to quantitatively characterize the measure of chemical compositions and structural features in dictating antimicrobial efficacy. FAI is a ratio of numbers of charges to rings, representing both compositions of hydrophilicity and hydrophobicity. Cationic derivatives of multicyclic compounds were evaluated as model systems for testing antimicrobial selectivity against Gram-negative and Gram-positive bacteria. Both monocyclic and bicyclic compounds are non-antimicrobial regardless of FAIs. Antimicrobial efficacy was observed with systems having larger cross-sectional areas including tricyclic abietic acid and tetracyclic bile acid. While low and high FAIs respectively lead to higher and lower antimicrobial efficacy, in consideration of cytotoxicity, the sweet spot is typically suited with intermediate FAIs for each specific system. This can be well explained by the synergistic hydrophobic-hydrophobic and electrostatic interactions with bacterial cell membranes and the difference between bacterial and mammalian cell membranes. The adoption of FAI would pave a new avenue toward the design of next-generation antimicrobial macromolecules and peptides.
Organic quantum dots: An ultrasmall nanoplatform for cancer theranostics
Authors: Namdev Dhas, Monarch Pastagia, Akanksha Sharma, Alisha Khera, Ritu Kudarha, Sanjay Kulkarni, Soji Soman, Srinivas Mutalik, Ravi Pratap Barnwal, Gurpal Singh, Mital Patel
Journal: Journal of Controlled Release (2022)
Rare germline alterations of myeloperoxidase predispose to myeloid neoplasms
Authors: Sunisa Kongkiatkamon, Laila Terkawi, Yihong Guan, Vera Adema, Metis Hasipek, Tatiana Dombrovski, Milo Co, Wencke Walter, Hassan Awada, Yvonne Parker, Stephan Hutter, Simona Pagliuca, Carmelo Gurnari, Heesun J. Rogers, Manja Meggendorfer, Daniel J. Lindner, Torsten Haferlach, Valeria Visconte, Thomas LaFramboise, Babal K. Jha, Jaroslaw P. Maciejewski
Journal: Leukemia (2022)
Polio’s detection in London is a wake-up call
Authors: Nicholas C Grassly
Journal: BMJ (2022)

Polio's detection in London is a wake-up call Nicholas C Grassly professor of infectious disease and vaccine epidemiologyThe UK Health Security Agency (UKHSA) has declared a "national incident" after poliovirus was detected in London sewage. 1 Detection of poliovirus in UK sewage is not in itself an unprecedented occurrence: between one and three polioviruses are typically detected every year, representing separate importations of the virus into the UK by travellers.However, detection of the current virus since February, and genetic sequencing showing its ongoing evolution, indicate likely circulation in the community, and therein lies the concern.
Concerns regarding the title and abstract conclusion in a recent genome‐wide association study on Behçet's disease: comment on the article by Su et al
Authors: Muhammed Abdulkerim Sahin, Sinem Nihal Esatoglu
Journal: Arthritis & Rheumatology (2022)

Disclosureforms Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
OP0156 TOCILIZUMAB USE IN SYSTEMIC SCLEROSIS: SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: R. Dos-Santos, E. Guadalupe, D. Fernández Fernández, I. González Fernández, M. Sanchez-Wonenburger, P. Castro-Santamaria, A. Mata, J. L. Puga Guzmán, E. Perez-Pampín, A. Souto Vilas, A. Mera Varela
Journal: Annals of the Rheumatic Diseases (2022)

Background Systemic sclerosis (SSc) is a low-prevalent autoimmune disease with a heterogeneous presentation. Skin involvement is the most frequent symptom and its treatment is orphan, only attending at Raynaud’s phenomenon and classic immunosuppressive therapy for fibrosis. Lung implication is still remaining as the first cause of death. Interstitial lung disease (ILD) is the most frequent presentation and treatments most used includes cyclophosphamide and mycophenolate. 1 In 2021, the Food and Drug Administration (FDA) approved the first biologic therapy for ILD-SSc, tocilizumab (TCZ), based on 2 clinical trials. 2,3 Objectives To assess TCZ efficacy in SSc, either in ILD or skin involvement. Methods A systematic literature review was made using Medline, Embase, Cochrane Library and the Web of Science databases. Search strategy focused in synonyms of SSc and TCZ, also including MeSH terms. A random-effects model meta-analysis was performed to evaluate TCZ efficacy, when comparable measures were found. Clinical trials, observational studies and case-series were eligible. Results Search strategy identified 1036 articles, finally 13 studies were eligible for the review. Regarding the effect of TCZ in SSc skin involvement, measured by the modified Rodnan Skin Score (mRSS), a non-significant 40% improvement in mRSS and change in mean mRSS was reported (OR 1.22 [0.74-2.01], p=0.43 and SMD -0.69 [-1,48-0.10], p=0.09, respectively). About ILD-SSc, a significant non-worsening 10% Forced Vital Capacity (FVC) was reported in patients treated with TCZ (OR 0.45 [0.23-0.86), p=0.02) (Figure 1). As well, a non-significant Diffusing capacity for carbon monoxide (DLCO) was observed in patients treated with TCZ (SMD -0.66 [-1.48- -0.17], p=0.12). Figure 1. Conclusion Our study is the first review and meta-analysis of SSc patients treated with TCZ. This results show that TCZ could delay the worsening of ILD-SSc, being one therapeutic alternative to classical immunosuppressive therapy. Further studies are needed for better disease understanding and TCZ implications in other organ impairment. References [1]Desbois AC, Cacoub P. Systemic sclerosis: An update in 2016. Autoinmun Rev. 2016 May; 15 (5): 417-26. [2]Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (fascinate): a phase 2, randomized, controlled trial. Lancet, 2016;387(10038):2630-2640. [3]Khanna D, Lin CJF, Furst DE, et al. Tocilizumab in systemic sclerosis: a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020;8(10):963-974. Disclosure of Interests None declared
OP0087 INTEGRATED SYSTEMS ANALYSIS OF THE GUT MICROBIOTA PHENOTYPES IN THE RHEUMATOID ARTHRITIS
Authors: J. Qiao, S. X. Zhang, M. J. Chang, S. Song, R. Zhao, T. Cheng, Y. Zhang, X. Li
Journal: Annals of the Rheumatic Diseases (2022)

Background Patients with rheumatoid arthritis (RA) displays extreme dysbiosis in microbiota. However, such dysbiosis is difficult to characterize owing to the high dimensional complexity of the gut microbiota 1,2 . Objectives The aim of this study was to discover the enterotype characters of intestinal flora in RA. Methods Fecal samples from 145 RA patients were collected for bacterial 16S rRNA genes sequencing. Mathematical modeling using Dirichlet multinomial mixtures (DMM) was applied to describe the variability in the microbiome data and cluster samples into enterotypes. The alpha-diversity, beta-diversity and the microbial composition analysis of the gut microbiome were used to define the difference of gut microbiota profiles between different enterotypes. The nonredundant taxonomic biomarkers for each enterotype were selected by using LEfSe. Inflammatory biomarkers (ESR, CRP), auto-antibodies(ACPA, MCV), peripheral lymphocytes subsets and cytokines were analyzed in our cohort using the Kruskal-Wallis test. Results Laplace approximation of DMM indicated two significantly distinct bacterial microbiota structures (RAE1 and RA E2) existed in the dataset (Figure 1a). Principal co-ordinates analyses confirmed that these two microbiota states explained a reasonable proportion of observed variance in microbiota composition(ANOSIM R2 = 0.267, p = 0.001; Figure 1b), with distinct bacterial genus distribution of in each enterotype (Figure 1c). RA E1 were primarily dominated by Prevotella while RA E2 by Bacteroides. Interestingly, Chao1, ACE, Shannon and Simpson revealed a higher alpha diversity in Prevotella-enriched enterotype (p&lt; 0.001, Figure 1d). Fourteen selected taxonomic biomarkers at different phylogenetic levels showed great discriminant ability, with Log10 LDA score &gt; 4.0 (Figure 1e-g). Further, inflammatory biomarkers (ESR, CRP) and auto-antibodies(ACPA, MCV) as well as the number of T, B and CD4+T, Th1, Th2, Th17, and Treg were consistent in RA E1 and RA E2 (p &gt; 0.05, Figure 2h). But CD8+T were significantly higher in RA E2 than in RA E2 (p &lt; 0.05). Conclusion Despite RA gut microbiota being of different dysbiosis, two patterns of dysbiosis, designated as RA-enterotypes, were predominant among the RA patient cohort. RA E2 exhibited a loss of Prevotella but a growth of Bacteroides, while RA E1 presented the opposite results. References [1]Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature 2011;473(7346):174-80. doi: 10.1038/nature09944 [2]Costea PI, Hildebrand F, Arumugam M, et al. Enterotypes in the landscape of gut microbial community composition. Nat Microbiol 2018;3(1):8-16. doi: 10.1038/s41564-017-0072-8 Acknowledgements This work was supported by the National Natural Science Foundation of China (No. 82001740). Disclosure of Interests None declared.